DESCRIPTION: (Applicant's Abstract) Problems associated with methamphetamine (METH) abuse have increased dramatically in the U.S. due to its escalating illicit use. To elucidate the responses to this drug and possibly identify novel therapeutic strategies for dealing with these problems, the relationship between extrapyramidal neuropeptide systems and the effects of this potent stimulant has been studied. It was observed that a low dose of METH (0.5 mg/kg) selectively influenced neurotensin (NT) systems in the dorsolateral caudate by activating dopamine D-2 receptors. In contrast, high doses of METH (10-15 mg/kg) selectively altered NT systems associated with the medial/ventral caudate by activating dopamine D-1 receptors. Because D-2 and D-1 dopamine receptors are selectively expressed in the striatal-pallidal and striatal-nigral neurons, respectively, these findings led to the hypothesis that low and high doses of METH preferentially influence the indirect (striatal-pallidal) and direct (striatal-nigral) efferent pathways to the basal ganglia output nuclei, respectively. This hypothesis will be tested by achieving the following Specific Aims: A. Determine if low doses of METH preferentially alter the activity of the indirect striatal efferent pathway to the globus pallidus. The effects of low doses of METH on associated transmitter systems (i.e., NT, met-enkephalin [M-enk] and GABA) will be monitored by measuring drug-induced changes in neurotransmitter (a) tissue content (NT and M-enk), (b) precursor mRNA levels (NT and M-enk), and (c) in vivo release (NT, M-enk and GABA). The role of the D-2 receptor in these effects will be elucidated. B. Determine if high doses of METH preferentially alter the direct striatal efferent projection to the substantia nigra. The effects of high doses of METH on associated transmitter systems (i.e., NT, substance P [SP] and GABA) will be monitored by measuring drug-induced changes in neurotransmitter (a) tissue content (NT and SP), (b) precursor mRNA levels (NT and SP), and (c) in vivo release (NT, SP and GABA). The role of the D-1 receptor in these effects will be elucidated. In addition, the role of striatal cholinergic interneurons in the effects identified from Specific Aims A and B will be studied. These studies may lead to a better appreciation of the neurobiology of these systems and improved therapies for problems associated with METH abuse as well as extrapyramidal/limbic dysfunctions.